Human parvovirus B19 (B19V) is the etiological agent of fifth disease seen in children, aplastic crisis in sickle cell disease patients, chronic anemia in immunocompromised patients, and hydrops fetalis in pregnant women. 35 years after its discovery, it was still not possible to propagate B19V in vitro in a productive and sustainable manner, which delayed progress in the study of B19V pathogenesis, and consequently finding ways to treat patients infected with B19V.

Researchers cultured human erythroid progenitor cells under hypoxic conditions by mimicking the natural niches of human bone marrow. This work demonstrates, for the first time, a long-term B19V infection of ex vivo expanded erythroid progenitor cells. This finding will largely facilitate the study of the mechanisms underlying B19V infection and more importantly, identification of approaches to treat B19V infection. Identification of the cellular signaling pathways in regulating B19V replication sheds light on the virus-host interaction and will nominate potential candidates for anti-virus drug targeting.

Productive Parvovirus B19 Infection of Primary Human Erythroid Progenitor Cells at Hypoxia Is Regulated by STAT5A and MEK Signaling but not HIFα. (2011) PLoS Pathog 7(6): e1002088. doi:10.1371/journal.ppat.1002088
Human parvovirus B19 (B19V) causes a variety of human diseases. Disease outcomes of bone marrow failure in patients with high turnover of red blood cells and immunocompromised conditions, and fetal hydrops in pregnant women are resulted from the targeting and destruction of specifically erythroid progenitors of the human bone marrow by B19V. Although the ex vivo expanded erythroid progenitor cells recently used for studies of B19V infection are highly permissive, they produce progeny viruses inefficiently. In the current study, we aimed to identify the mechanism that underlies productive B19V infection of erythroid progenitor cells cultured in a physiologically relevant environment. Here, we demonstrate an effective reverse genetic system of B19V, and that B19V infection of ex vivo expanded erythroid progenitor cells at 1% O2 (hypoxia) produces progeny viruses continuously and efficiently at a level of approximately 10 times higher than that seen in the context of normoxia. With regard to mechanism, we show that hypoxia promotes replication of the B19V genome within the nucleus, and that this is independent of the canonical PHD/HIFα pathway, but dependent on STAT5A and MEK/ERK signaling. We further show that simultaneous upregulation of STAT5A signaling and down-regulation of MEK/ERK signaling boosts the level of B19V infection in erythroid progenitor cells under normoxia to that in cells under hypoxia. We conclude that B19V infection of ex vivo expanded erythroid progenitor cells at hypoxia closely mimics native infection of erythroid progenitors in human bone marrow, maintains erythroid progenitors at a stage conducive to efficient production of progeny viruses, and is regulated by the STAT5A and MEK/ERK pathways.